Iontophoresis system

ABSTRACT

The present invention relates to an iontophoresis system. A power supply circuit for applying pulsating voltages to iontophoretic elements includes an element selector and a potential difference generating unit. The element selector selects a combination of iontophoretic elements according to given timing. The potential difference generating unit generates a potential difference between a selected combination of iontophoretic elements by applying pulsating voltages to the iontophoretic elements at different time periods. When the system is in operation, the iontophoretic elements will not be kept at a certain potential and undesirable electrode reactions can be prevented from occurring at each iontophoretic element.

TECHNICAL FIELD

The present invention relates to an iontophoresis system forpercutaneously administering a medicine by means of an electric current.

BACKGROUND ART

An iontophoresis system comprises a pair of iontophoretic elements(hereinafter elements) each containing, for example, an ionic drug ormedicine, and a power source for applying pulsating voltages to theelements. In the system, the elements are placed on the skin, and thenpulsating voltages are applied to the elements. An electrically-closedcircuit is thus formed via the skin, whereby a medicine is introducedinto a human body. The conductivity of the thus formed electricallyclosed circuit is dependent greatly on the states of the elementscontacting the skin. The electrodes in the elements, which are connectedto the power source, are deposited in the same environment as a fluidcontaining an ionic drug or medicine. Besides, when the system is inoperation, voltages that are pulsating in one direction are appliedintermittently to the electrodes. Therefore, the electrodes may undergochemical changes, or electrolysis or adhesion of electrically insulatingmaterials may occur at the surfaces of the electrodes.

The conductivity of the electrically closed circuit thereforedeteriorates with the variations of the states of the electrodes in theelements in the system. The persistence of the efficacy of themedication is therefore impaired.

DISCLOSURE OF THE INVENTION

The objects of the present invention are to provide an iontophoresissystem in which electrodes in the elements are not susceptible to theinfluence of electrode reactions such as chemical changes andelectrolysis, and to improve the persistence of efficacy of medication.

According to the present invention, an iontophoresis 5 system comprisesat least three elements any or all of which contain a medicine, and apower supply means for applying pulsating voltages to any pair ofelements so as to generate a potential difference between the pair ofelements. The power supply means includes a device selecting means forselecting a combination of elements from among the at least threeelements according to a given timing, and a potential differencegenerating means for generating a potential difference between aselected combination of elements by applying pulsating voltages to theelements over different time periods.

In a preferred embodiment of the present invention, the potentialdifference generating means preferably generates potential differencesbetween selected combinations of elements by applying a voltage, whichis opposite in polarity to the polarity of a voltage applied to at leastone of the elements which was selected previously, to the element. Thedevice selecting means preferably selects combinations of elements, in agiven order, cyclically.

In another preferred embodiment of the present invention, a selectedcombination of elements is a pair of elements. The potential differencegenerating means preferably retains any element other than the selectedelements in an electrically neutral state.

In yet another preferred embodiment of the present invention, the atleast three elements are in one package.

According to the foregoing embodiments of the present invention, anycombination of elements is selected according to a given timing. Apotential difference is generated between combinations of elements byapplying pulsating voltages to the elements at different time periods.The phase of a pulsating voltage to be applied to each element isinverted according to the given timing and the electrodes in theelements are renewed. Thus the aforesaid problem concerning electrodereactions is solved.

When a combination of elements is a pair of elements, the phase of apulsating voltage to be applied to each element is inverted efficientlyand effectively.

Moreover, since any element other than the selected elements is retainedin an electrically neutral state, the power consumption of a powersource in the system can be minimized.

According to the present invention, the electrodes in the elements canbe refreshed and the occurrence of electrode reactions in the electrodescan be avoided or suppressed. This system thus provides stablepercutaneous medication for a prolonged period of time.

BRIEF DESCRIPTION OF THE DRAWINGS

The aforesaid object and other objects, features, and advantages of thepresent invention will be described in detail in conjunction with theappended drawings.

FIG. 1 is a bottom view showing a first embodiment of an iontophoresissystem in accordance with the present invention;

FIG. 2 shows an X-X' section of the system shown in FIG. 1;

FIGS. 3 lines 1 to 35 are timing charts showing voltages applied torespective components of the system shown in FIG. 1, wherein (1) shows apulsating voltage supplied from a pulsating voltage producing circuit toelements 11 and 12, (2) shows a pulsating voltage supplied from thepulsating voltage producing circuit to elements 12 and 13, (3) shows apulsating voltage supplied from the pulsating voltage producing circuitto the elements 13 and 11, (4) shows voltage fluctuations occurring atthe elements 11 and 12, and (5) shows voltage fluctuations occurring atthe elements 11 and 12 when pulsating voltages are applied according toanother method;

FIG. 4 is a circuit diagram showing an example of a pulsating voltageproducing circuit in a power supply unit shown in FIG. 1; and

FIG. 5 is a bottom view showing a second embodiment of an iontophoresissystem in accordance with the present invention.

BEST MODE FOR CARRYING OUT THE INVENTION

To begin with, the configuration of the first embodiment of aniontophoresis system in accordance with the present invention will bedescribed in conjunction with FIGS. 1 and 2.

An iontophoresis system of this embodiment comprises an iontophoreticelement unit 1 (hereinafter an element unit) to be placed on the skin ofa living body, and a power supply unit 2 for supplying pulsatingvoltages to the unit 1. The element unit 1 is composed of elements 11,12, and 13 to be connected to the power supply unit 2 by way of powerlines A, B, and C, and an adherent section 14 for retaining the elementunit 1 on the skin of a living body by means of adhesion. The elements11, 12, and 13 and the adherent section 14 are covered with a package15. The power supply unit 2 includes a power source 21 that is a batteryor any other appropriate source, a pulsating voltage producing circuit22 for producing pulsating voltage outputs, and a control unit 23 forcontrolling the pulsating voltage producing circuit 22.

In this embodiment, the element unit 1 and power supply unit 2 areseparated from each other. Alternatively, the element unit 1 and powersupply unit 2 may be integrated into one unit. In this case, the powersupply unit 2 must be designed compactly using a button cell and anintegrated circuit.

In this embodiment, the elements have the same shape. Each or any of theelements contains a drug or medicine. The element 11 or 12 is, as shownin FIG. 2, composed of an electrode 111 or 112 connected to the powersupply unit 2 and an interfacing member 121 or 122 containing a drug ormedicine.

The electrodes 111 and 112 are made of a conductive material,preferably, an inactive raw material such as Ag--AgCl. The conductivematerial is not limited to Ag--AgCl. The interfacing members 121 and 122are formed with a porous member or a conductive gel. A preferableexample of the porous member is a film member having water absorbency orwater permeability, for example, a laminated membrane filter (Biodyne A(trade mark)), a nonwoven fabric, a multilayer member made of waterpermeable fibers; such as, a porous film, (for example, a wafer) starchcomposed of water-soluble high molecular weight materials and capable ofholding, adhering, or encapsulating a given drug or medicine, or awater-absorbent (or -soluble) film such as a PVP film.

The degree of the water solubility of a porous member and the content ofa drug or medicine in the porous member are specified or adjustedappropriately according to the purpose of the iontophoresis system.

Next, the operations of the iontophoresis system will be described inconjunction with FIG. 3.

After the element unit 1 is placed on an object region for medication onthe skin, the power supply unit 2 is energized. The power supply unit 2applies pulsating voltages, which can be set to any value ranging fromseveral volts to several tens of volts, to the elements 11 and 12 by wayof the lead wires A and B respectively. At this time, the power supplyunit 2 applies the pulsating voltages so as to cause the potential atthe element 11 to go high (positive) and the potential at the element 12to go low (negative), and thus generates a potential difference betweenthe elements 11 and 12. After applying the pulsating voltages to theelements 11 and 12, the power supply unit 2 applies pulsating voltagesto the elements 12 and 13 by way of the lead wires B and C according togiven timing (See FIG. 3(2)). At this time, the power supply unit 2applies the pulsating voltages so as to cause the potential at theelement 12 to go high (positive) and the potential at the element 13 togo low (negative), and thus generates a potential difference between theelements 12 and 13. After applying the pulsating voltages to theelements 12 and 13, the power supply unit 2 applies pulsating voltagesto the elements 13 and 11 by way of the lead wires C and A synchronouslywith a given voltage (See FIG. 3(3)). At this time, the power supplyunit 2 applies the pulsating voltages so as to cause the potential atthe element 13 to go high (positive) and the potential at the element 11to go low (negative), and thus generates a potential difference betweenthe elements 13 and 11.

Thereafter, the power supply unit 2 repeatedly executes the foregoingsequence of pulsating voltage application by inverting the phase of apulsating voltage to be applied to each element. FIG. 3(4) shows voltagefluctuations occurring at the elements 11 and 12 during the sequence.The potential generating means generates positive pulses each having amaximum duty cycle, i.e., time duration of the positive pulse as a ratioto the total time period between leading edges of the positive pulses,equal to 1/n, wherein n is equal to the number of iontophoreticelements. In the described embodiment, the maximum duty ratio of voltagepulses applied to any one pair of elements selected from the threeelements is 33%. In the embodiment of FIG. 5, yet to be described, withfour elements, the duty cycle is 25%. Since the phase of a pulsatingvoltage to be applied to each element is inverted during each period ofapplication, electrode reactions causing the conductivity of eachelement to deteriorate can be avoided and the occurrence of polarizationcharge causing a burn can be prevented.

Next, the configuration of the power supply unit 2 producing theaforesaid sequence of pulsating voltages will be described inconjunction with FIGS. 1 to 4.

The power supply unit 2 is, as shown in FIG. 1, composed of the powersource 21 such as a battery, the control unit 23, and the pulsatingvoltage producing circuit 22 for producing pulsating voltages inresponse to a signal sent from the control unit 23.

The control unit 23 can be realized with one or a plurality of one-chipmicrocomputers each comprising, for example, a CPU, a clock generator, avoltage divider for producing a pulsating signal of a given frequency onthe basis of a clock generated by the clock generator, a memory meansfor storing a program for executing the sequence of pulsating voltageapplication and coefficients to be specified in the program, and aninterface means for providing an interface with the pulsating voltageproducing circuit. The control unit 23 feeds a first pulsating signal ofa given frequency to an input port 4a of the pulsating voltage producingcircuit, and a second pulsating signal, which lags behind the firstpulsating signal by a given time, sequentially to input ports 4b to 4d.The first pulsating signal is used to cause the pulsating voltageproducing circuit 22 to produce a high voltage. The second pulsatingsignal is used as a select signal enabling selective application of apulsating voltage to the elements.

The frequency of the first pulsating signal fed to the input port 4aranges, for example, from 1 kHz to 10 MHz. The frequency of the secondpulsating signal fed to each of the input ports 4b to 4d is, forexample, several tens of kHz. These pulsating signals are produced bythe voltage divider in the control circuit 23. Alternatively, anoscillator such as a multivibrator may be used for producing thepulsating signals. A pulsating signal having a frequency of 40 kHz and aduty ratio of about 30% is supplied, as an output resulting from phaseinversion, to each of the input ports 4b to 4d.

The pulsating voltage producing circuit 22 is, as shown in FIG. 4,composed of a plurality of switching transistors 41 and 44 to 49, aninductor 42, and a capacitor 43. The power source 21 such as a batteryshown in FIG. 1 is connected to a terminal BAT of the pulsating voltageproducing circuit 22. The elements 11, 12, and 13 are connected to theoutput ports 4A to 4C by way of the lead wires A to C.

The operations of the pulsating voltage producing circuit 22 will bedescribed below.

When a first pulsating signal is fed to the input port 4a, thetransistor 41 is turned on or off synchronously with the pulsatingsignal. When the transistor 41 is turned on, an excitation current flowsinto the inductor 42. When the transistor 41 is turned off, a boostedpulse whose level is several times to several tens of times larger thanthe supply voltage is generated due to the energy released by theinductor 42. The boosted pulse is stored in the capacitor 43 via adiode, and then used as pulsating power to be applied to each element.

When a second pulsating signal, serving as a select signal, is fed fromthe control unit to the input port 4b, the transistor 47 is turned on atthe leading edge of the select signal. The transistor 44 is turned onsynchronously with the transistor 47. The voltage stored in thecapacitor 43 is then delivered to each of the output ports 4A and 4B.Thereafter, when the select signal fed to the input port 4b is drivenlow, the transistors 44 and 47 are turned off. Application of voltagesto the elements 11 and 12 via the output ports 4A and 4B is thenterminated. Thus, pulsating voltages corresponding to the select signalare applied to the elements 11 and 12.

A given time later, when another select signal is fed from the controlunit 23 to the input port 4c, the transistors 45 and 48 are activated. Apulsating voltage causing the potential at the output port 4B to go highis delivered to each of the output ports 4B and 4C. Output pulsatingvoltages are then applied to the elements 12 and 13.

A given time later, when yet another select signal is fed from thecontrol unit 23 to the input port 4d, the transistors 46 and 49 areactivated. A pulsating voltage causing the potential at the output port4C to go high is delivered to each of the output ports 4C and 4A. Outputpulsating voltages are then applied to the elements 13 and 11.

Note that since the pulsating voltage producing circuit 22 has theaforesaid circuitry, the potentials at the output ports are invertedwith every input of a select signal from the control unit 23.

As mentioned above, select signals that lag behind previous signals bygiven times are consecutively applied to the input ports 4b, 4c, and 4d.A pulsating voltage, whose phase is inverted, is fed sequentially to anypair of the output ports 4A, 4B, and 4C. Consequently, a pulsatingvoltage whose phase is inverted is applied sequentially to each pair ofthe elements 11, 12, and 13.

The second embodiment of an iontophoresis system in accordance with thepresent invention will be described in conjunction with FIG. 5.

An iontophoresis system shown in FIG. 5 has four elements. Theconfiguration and inner structure are identical to those shown in FIGS.1 and 2. The description of the configuration and inner structure willtherefore be omitted. Any medicine can be contained in each of theelements 51, 52, 53, and 54.

The application of pulsating voltages in this embodiment will bedescribed. First, a pair of the elements 51 and 52 is selected with afirst select signal fed from a control unit 23' in the power supply unit2. A pulsating voltage producing circuit 22' applies pulsating voltagesto the elements 51 and 52, thus causing the potential at the element 51to go high (positive) and the potential at the element 51 to go low(negative). With another select signal, a pair of the elements 53 and 54is selected. Pulsating voltages are then applied to the elements 53 and54, thus causing the potential at the element 53 to go high and thepotential at the element 54 to go low. A pair of the elements 54 and 51is selected with the next select signal. This causes the potential atthe element 54 to go high and the potential at the element 51 to go low.A pair of the elements 52 and 53 is then selected with another selectsignal. This causes the potential at the element 52 to go high and thepotential at the element 53 to go low. By executing the foregoingsequence repeatedly, a pulsating voltage is applied to an element, towhich a previous pulsating voltage is applied via an output port whosepotential is driven high, via the output port whose potential is drivenlow. Through the applications of pulsating voltages, the elements arenot kept at either a high or a low potential. Electrode reactionscausing conductivity to deteriorate can be prevented from occurring atthe electrode in each element.

According to the present invention, the number of elements and the wayof combining the elements are not limited to those in the aforesaidembodiments. Alternatively, five or more elements may be employed, and aplurality of elements may be paired with one element for the applicationof pulsating voltages. The configuration required for this alternativewill be apparent, from the embodiments, to a person with an ordinaryskill in the art. When the number of elements is increased, the numbersof input ports, output ports, and transistors shown in FIG. 4 should beincreased accordingly. When a plurality of elements are paired with oneelement for application of pulsating voltages, a known diode matrixcircuit or the like is used to select any of the transistors associatedwith the input ports and output ports shown in FIG. 4.

The order of applying pulsating voltages to elements, application times,timing, and combinations of elements can be changed by modifying aprogram written in a microcomputer employed in the aforesaidembodiments. For example, a pulse duration of a pulsating voltageapplied to each element may be shortened as indicated with dashed linesT in FIGS. 3(1) to 3(3) and as shown in FIG. 3(5), and then a periodbetween pulses may be regarded as a quiescent period. Owing to thedefinition of the quiescent period, the power consumption of a powersupply unit can be minimized. This results in a compact system.

In the aforesaid embodiments, a plurality of elements are stowed in anelement unit. Alternatively, the elements may be formed as stand-alonedevices.

Finally, examples of drugs and medicines usable for an iontophoresissystem in accordance with the present invention will be listed below.

Local anesthetic

(lidocaine hydrochloride, tetracaine hydrochloride, procainehydrochloride, dibucaine hydrochloride, oxyprocaine hydrochloride,bupivacaine hydrochloride, mepivacaine hydrochloride, etc.)

Antiallergic agent or antitussant and expectorant

(sodium cromoglycate, ketotifen fumarate, azelastine hydrochloride,amlexanox, terfenadine, emedastine, fumarate, tranilast, codeinephosphate, dihydrocodeine phosphate, eprazinone hydrochloride,tipepidine hybenzate, etc.)

Bronchial dilator

(theophylline, pirbuterol hydrochloride, terbutaline sulfate,hexoprenaline sulfate, salbutanol sulfate, tulobuterol hydrochloride,procaterol hydrochloride, mabuterol hydrochloride, formoterol fumarate,etc.)

Analgesic

(morphine hydrochloride, hydromorphone hydrochloride, buprenorphinehydrochloride, bupranolol hydrochloride, pentazocine, butorphanoltartrate, eptazocine hydrobromide, nalbuphine hydrochloride, etc.)

Cardiac

(dopamine hydrochloride, dobutamine hydrochloride, amrinone, etc.)

Tranquilizer

(chlorpromazine hydrochloride, etizolam, amitriptyline hydrochloride,clocapramine dihydrochloride, haloperidol, mosapramine hydrochloride,perphenazine, etc.)

Antibiotic

(penicillin antibiotics such as cloxacillin sodium, benzylpenicillinpotassium, ticarcillin sodium, ampicillin sodium, and piperacillinsodium; cefm antibiotics such as cefoxitin sodium, cefodizime sodium,cefotaxime sodium, cefotetan, cefoperazone sodium, cefsulodin sodium,ceftazidime, cefmetazole sodium, and cefpirome sodium; amino sugarantibiotics such as gentamicin sodium, sisomicin sodium, dibekacinsodium, netilmicin sodium, amikacin sodium, and ribostamycin sodium;other antibiotics such as lincomycin, erythromycin, josamycin,chloramphenicol, and tetracycline)

Antimelanoma agent

(mitomycin C, etoposide, procarbazine hydrochloride, tamoxifen citrate,fluorouracil, UFT, tegafur, carmofur, methotrexate, carboquone,bleomycin hydrochloride, peplomycin sulfate, epirubicin hydrochloride,pirarubicin hydrochloride, neocarzinostatin, lentinan, picibanil,sizofilan, cisplatin, carboplatin, adriamycin, vincristine sulfate,etc.)

Circulatory medicine

(nicametate citrate, alprostadil, argatroban, citicoline, nizofenonefumarate, D-mannitol, nicorandil, diltriazem hydrochloride, etc.)

Gout treatment agent

(benzbromarone, allopurinol, colchicine, etc.)

High lipemia agent

(simvastatin, nicomol, pravastatin sodium, etc.)

Antihistamine

(diphenhydramine hydrochloride, promethazine hydrochloride,chlorpheniramine maleate, mequitazine, clemastine fumarate, etc.)

Sleep abirritant or antianxiety agent

(flunitrazepam, midazolam, secobarbital sodium, amobarbital sodium,phenytoin sodium, etc.)

Analgesic or antiphlogistic

(ketoprofen, flurbiprofen axetil, indometacin, loxoprofen sodium,diclofenac sodium, piroxicam, tenidap, flurbirpfen, tenoxicam, etc.)

Anti-dizziness agent

(difenidol hydrochloride, thiethylperazine maleate, beta-histinemesylate, etc.)

Anticonvulsant

(scopolamine buthylbromide, atropine sulfate, eperisone hydrochloride,tizanidine hydrochloride, etc.)

Arrhythmia agent

(arotinolol hydrochloride, propranolol hydrochloride, atenolol,quinidine sulfate, indenolol hydrochloride, bucumolol hydrochloride,etc.)

Antihypertensive agent

(clonidine hydrochloride, bethanidine sulfate, benazepril hydrochloride,cilazapril, captopril, celiprolol hydrochloride, tilisololhydrochloride, terazosinn hydrochloride, bunnazosin hydrochloride,carvedilol, etc.)

Cortical hormone

(hydrocortisone sodium phosphate, dexamethasone palmitate, dexamethasonesodium phosphate, betamethasone sodium phosphate, methylprednisolonesuccinate, etc.)

Peptide, polypeptide, and other drugs include luteinizinghormone-releasing hormone (LH-RH), enkephalin, endorphin, interferon,insulin, calcitonin, thyrotropin releasing hormone (TRH), oxytocin,lypressin, vasopressin, glucagon, pituitary hormone (human growthhormone (HGH), human menopausal gonadotrophin (HMG), human chorionicgonadotrophin (HCG), desmopressin acetate), follicile stimulatinghormone, growth hormone releasing factor, adrenocorticotropic hormone(ACTH), parathyroid hormone (PTH), secretin, angiotensin,beta-endorphin, somatostatin, gastrin, neurotensin, atrial natriureticpeptide (ANP), bradykinin, substance P, dynorphin, thyroid-stimulatinghormone (TSH), prolactin, interleukin, granulocyte colony-stimulatingfactor (G-CSF), glutathione peroxidase, superoxide dismutase (SOD),desmopressin, somatomedin, melanocyte-stimulating hormone (MSH), muramyldipeptide, bombesin, vasoactive intestinal polypeptide,cholecystokinin-8, calcitonin gene relating peptide (CGRP), endothelin,and nicotine.

These agents are mixed with various matrix components available inpharmaceutics and can be used in various types of forms such as salve,gel, cream, solution, suspension, film, or the like.

I claim:
 1. An iontophoresis system having at least three iontophoreticelements, any or all of which contains a medicine, and a power supplymeans connected to the elements for applying pulsating voltages to theelements so as to generate a potential difference between the elements,wherein:said power supply means includes an element selecting means forcyclically selecting a pair of iontophoretic elements in a given orderfrom among said at least three iontophoretic elements, and a potentialdifference generating means for generating a potential differencebetween said selected pairs of iontophoretic elements by applyingpulsating voltages to the elements at different time instants; whereinsaid potential difference generating means retains any iontophoreticelement other than the selected iontophoretic elements in anelectrically neutral state; wherein said potential difference generatingmeans generates a potential difference by applying a voltage to one ofthe iontophoretic elements of one of said selected pairs ofiontophoretic elements such that said voltage pulsates in a directionopposite to a direction of a voltage previously applied to said one ofthe iontophoretic elements of a previously selected pair; and whereinsaid potential difference generating means generates potentialdifferences so that each of any one pair of iontophoretic elementsselected from among the at least three elements exhibits a voltage ofthe same polarity, and so that the polarity of each of the elements isperiodically changed to the three states of positive polarity, negativepolarity and electrically neutral.
 2. The system according to claim 1,wherein said at least three iontophoretic elements are stowed in onepackage.
 3. The iontophoresis system of claim 1 wherein a duty ratio ofvoltage pulses applied to any one pair of elements selected from amongthe at least three electrodes corresponds to an inverse number or lessof the number of elements.
 4. The iontophoresis system of claim 1wherein the potential generating means generates positive pulses havinga maximum duty cycle equal to 1/n, wherein n is equal to the number ofiontophoretic elements.
 5. An iontophoresis system having at least threeiontophoretic elements, any or all of which contains a medicine, and apower supply means connected to the elements for applying pulsatingvoltages to the elements so as to generate a potential differencebetween the elements wherein:said power supply means includes an elementselecting means for cyclically selecting pairs of iontophoretic elementsin a given order from among said at least three iontophoretic elements,and a potential difference generating means for generating a potentialdifference between said iontophoretic elements of said selected pairs byapplying a positive pulse to one iontophoretic element and a negativepulse to the other iontophoretic element of said selected pair andretaining any iontophoretic elements other than the selected pair in anelectrically neutral state, wherein said potential difference generatingmeans generates said potential difference so that each of theiontophoretic elements of a selected pair always receives the samepolarity pulse when said pair is selected by the element selectingmeans, each of the iontophoretic elements receiving a periodic waveformcomprising a positive pulse, a negative pulse and electrically neutralstate.